tbuckley/cabot-search huggingface dataset:
Letter to the editor: Aspirin use and the risk of hepatocellular carcinoma
Authors: Shih‐Wei Lai
Journal: Hepatology (2022)

To the editor, The test of aspirin on primary prevention of hepatocellular carcinoma is ongoing. A cohort study conducted by Dr. Jang and colleagues revealed that a lower risk of hepatocellular carcinoma was noted among adults with chronic hepatitis B infection who took aspirin when comparing with adults with chronic hepatitis B infection who did not take antiplatelet agents (hazard ratio, 0.85; 95% confidence interval, 0.78–0.92).[1] These findings were partially compatible with previous research.[2] Some questions are discussed. If the immortal time is not handled properly, the research results will be presented in the wrong way.[3] Some authors included the immortal time into the treated group, but some authors directly excluded the immortal time from the study.[4] All of these approaches might create an overestimation of drug benefit.[3] Although Dr. Jang and colleagues used some adjustments to avoid the immortal time bias, some points remain unclear. In Figure 1, I create two cases using the same methods of the treated group mentioned in Dr. Jang and colleagues' study.[1] In case A, the first use of aspirin was prescribed for 90 consecutive days and the index date was set to the 180th day after the first date of aspirin prescription. Then, case A was not prescribed with aspirin until the study end. Under this situation, how does one avoid the immortal time bias? Was case A still included in the treated group? In case B, the first use of aspirin was prescribed for 90 consecutive days and the index date was set to the 180th day after the first date of aspirin prescription. Later, case B restarted to be prescribed with aspirin till the study end. Obviously, there were 180 days without prescription of aspirin; this was the immortal time. Under this situation, may I ask whether the immortal time was excluded directly from the study, or was the immortal time counted into the treated group or the untreated group? The purpose of the letter is to communicate medical findings with Dr. Jang and colleagues, not criticize their research. Due to the limitations of word number and figure number for the letter to the editor, I cannot write too much. If my interpretation is wrong, please correct it. I will appreciate Dr. Jang and colleagues' answer and correction.FIGURE 1: Two assumed cases in the treated group. Gray color is the immortal time.AUTHOR CONTRIBUTIONS Shih‐Wei Lai contributed to the conception of the article and initiated the draft of the article. CONFLICT OF INTEREST Nothing to report.
The Mini Colon Model: a benchtop multi-bioreactor system to investigate the gut microbiome
Authors: Zijie Jin, Andy Ng, Corinne F. Maurice, David Juncker
Journal: Gut Microbes (2022)

In vitro fermentation systems allow for the investigation of gut microbial communities with precise control of various physiological parameters while decoupling confounding factors from the human host. Current systems, such as the SHIME and Robogut, are large in footprint, lack multiplexing, and have low experimental throughput. Alternatives which address these shortcomings, such as the Mini Bioreactor Array system, are often reliant on expensive specialized equipment, which hinders wide replication across labs. Here, we present the Mini Colon Model (MiCoMo), a low-cost, benchtop multi-bioreactor system that simulates the human colon environment with physiologically relevant conditions. The device consists of triplicate bioreactors working independently of an anaerobic chamber and equipped with automated pH, temperature, and fluidic control. We conducted 14-d experiments and found that MiCoMo was able to support a stable complex microbiota community with a Shannon Index of 3.17 ± 0.65, from individual fecal samples after only 3–5 d of inoculation. MiCoMo also retained inter-sample microbial differences by developing closely related communities unique to each donor, while maintaining both minimal variations between replicate reactors (average Bray-Curtis similarity 0.72 ± 0.13) andday-to-day variations (average Bray-Curtis similarity 0.81±0.10) after this short stabilization period. Together, these results establish MiCoMo as an accessible system for studying gut microbial communities with high throughput and multiplexing capabilities.
Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial
Authors: Andrew B Lassman, Stephanie L Pugh, Tony J C Wang, Kenneth Aldape, Hui K Gan, Matthias Preusser, Michael A Vogelbaum, Erik P Sulman, Minhee Won, Peixin Zhang, Golnaz Moazami, Marian S Macsai, Mark R Gilbert, Earle E Bain, Vincent Blot, Peter J Ansell, Suvajit Samanta, Madan G Kundu, Terri S Armstrong, Jeffrey S Wefel, Clemens Seidel, Filip Y de Vos, Sigmund Hsu, Andrés F Cardona, Giuseppe Lombardi, Dmitry Bentsion, Richard A Peterson, Craig Gedye, Véronique Bourg, Antje Wick, Walter J Curran, Minesh P Mehta
Journal: Neuro-Oncology (2022)

Abstract Background Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. Methods In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. Results There were 639 randomized patients (median age 60, range 22–84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82–1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70–1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61–0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3–4), causing 12% to discontinue. Conclusions Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.
T cell responses against SARS-CoV-2 and its Omicron variant in a patient with B cell lymphoma after multiple doses of a COVID-19 mRNA vaccine
Authors: Djordje Atanackovic, Robert J Kreitman, Jeffrey Cohen, Nancy M Hardy, Destiny Omili, Thierry Iraguha, Peter D Burbelo, Etse Gebru, Xiaoxuan Fan, John Baddley, Tim Luetkens, Saurabh Dahiya, Aaron P Rapoport
Journal: Journal for ImmunoTherapy of Cancer (2022)

Anti-SARS-CoV-2 antibodies are crucial for protection from future COVID-19 infections, limiting disease severity, and control of viral transmission. While patients with the most common type of hematologic malignancy, B cell lymphoma, often develop insufficient antibody responses to messenger RNA (mRNA) vaccines, vaccine-induced T cells would have the potential to ‘rescue’ protective immunity in patients with B cell lymphoma. Here we report the case of a patient with B cell lymphoma with profound B cell depletion after initial chemoimmunotherapy who received a total of six doses of a COVID-19 mRNA vaccine. The patient developed vaccine-induced anti-SARS-CoV-2 antibodies only after the fifth and sixth doses of the vaccine once his B cells had started to recover. Remarkably, even in the context of severe treatment-induced suppression of the humoral immune system, the patient was able to mount virus-specific CD4 + and CD8 + responses that were much stronger than what would be expected in healthy subjects after two to three doses of a COVID-19 mRNA vaccine and which were even able to target the Omicron ‘immune escape’ variant of the SARS-CoV-2 virus. These findings not only have important implications for anti-COVID-19 vaccination strategies but also for future antitumor vaccines in patients with cancer with profound treatment-induced immunosuppression.
TME-triggered MnSiO3@Met@GOx nanosystem for ATP dual-inhibited starvation/chemodynamic synergistic therapy
Authors: Jiayao Zhang, Chen Liang, Ziye Wei, Wanlan Yang, Wei Ge, Xinyu Qu, Weili Si, Wenjun Wang, Xiaozhou Mou, Xiaochen Dong
Journal: Biomaterials (2022)
Production of cultured meat from pig muscle stem cells
Authors: Haozhe Zhu, Zhongyuan Wu, Xi Ding, Mark J. Post, Renpeng Guo, Jie Wang, Junjun Wu, Wenlai Tang, Shijie Ding, Guanghong Zhou
Journal: Biomaterials (2022)

Cultured meat is meat for consumption produced in a more sustainable way. It involves cell harvesting and expansion, differentiation into myotubes, construction into muscle fibres and meat structuring. We isolated 5.3 × 104 porcine muscle stem cells from 1 g of neonatal pig muscle tissue. According to calculations, we need to expand muscle stem cells 106-107 times to produce 100 g or 1 kg of cultured meat. However, the cells gradually lost the ability to express stemness and mature muscle cell markers (PAX7, MyHC). To tackle this critical issue and maintain cell function during cell expansion, we found that long-term culture with (100 μM) l-Ascorbic acid 2-phosphate (Asc-2P) accelerated cell proliferation while preserving the muscle cell differentiation. We further optimized a scalable PDMS mold. Porcine muscle stem cells formed structurally-organized myotubes similar to muscle fibres in the mold. Asc-2P enhanced porcine muscle cells grown as 3D tissue networks that can produce a relatively large 3D tissue networks as cultured meat building blocks, which showed improved texture and amino acid content. These results established a realistic workflow for the production of cultured meat that mimics the pork meat structurally and is potentially scalable for industry.
Toll-like receptor 7/8 agonist R848 alters the immune tumor microenvironment and enhances SBRT-induced antitumor efficacy in murine models of pancreatic cancer
Authors: Jian Ye, Bradley N Mills, Shuyang S Qin, Jesse Garrett-Larsen, Joseph D Murphy, Taylor P Uccello, Booyeon J Han, Tara G Vrooman, Carl J Johnston, Edith M Lord, Brian A Belt, David C Linehan, Scott A Gerber
Journal: Journal for ImmunoTherapy of Cancer (2022)

Stereotactic body radiotherapy (SBRT) has been increasingly used as adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC), and induces immunogenic cell death, which leads to the release of tumor antigen and damage-associated molecular patterns. However, this induction often fails to generate sufficient response to overcome pre-existing tumor microenvironment (TME) immunosuppression. Toll-like receptor (TLR) 7/8 ligands, such as R848, can amplify the effect of tumor vaccines, with recent evidence showing its antitumor effect in pancreatic cancer by modulating the immunosuppressive TME. Therefore, we hypothesized that the combination of R848 and SBRT would improve local and systemic antitumor immune responses by potentiating the antitumor effects of SBRT and reversing the immunosuppressive nature of the PDAC TME.Using murine models of orthotopic PDAC, we assessed the combination of intravenous TLR7/8 agonist R848 and local SBRT on tumor growth and immune response in primary pancreatic tumors. Additionally, we employed a hepatic metastatic model to investigate if the combination of SBRT targeting only the primary pancreatic tumor and systemic R848 is effective in controlling established liver metastases.We demonstrated that intravenous administration of the TLR7/8 agonist R848, in combination with local SBRT, leads to superior tumor control compared with either treatment alone. The combination of R848 and SBRT results in significant immune activation of the pancreatic TME, including increased tumor antigen-specific CD8+ T cells, decreased regulatory T cells, and enhanced antigen-presenting cells maturation, as well as increased interferon gamma, granzyme B, and CCL5 along with decreased levels of interleukin 4 (IL-4), IL-6, and IL-10. Importantly, the combination of SBRT and systemic R848 also resulted in similar immunostimulatory changes in liver metastases, leading to improved metastatic control. CD8+ T cell depletion studies highlighted the necessity of these effector cells at both the local and hepatic metastatic sites. T cell receptor (TCR) clonotype analysis indicated that systemic R848 not only diversified the TCR repertoire but also conditioned the metastatic foci to facilitate entry of CD8+ T cells generated by SBRT therapy.These findings suggest that systemic administration of TLR7/8 agonists in combination with SBRT may be a promising avenue for metastatic PDAC treatment.
Debulking different Corona (SARS-CoV-2 delta, omicron, OC43) and Influenza (H1N1, H3N2) virus strains by plant viral trap proteins in chewing gums to decrease infection and transmission
Authors: Henry Daniell, Smruti K. Nair, Hancheng Guan, Yuwei Guo, Rachel J. Kulchar, Marcelo D.T. Torres, Md. Shahed-Al-Mahmud, Geetanjali Wakade, Yo-Min Liu, Andrew D. Marques, Jevon Graham-Wooten, Wan Zhou, Ping Wang, Sudheer K. Molugu, William R. de Araujo, Cesar de la Fuente-Nunez, Che Ma, William R. Short, Pablo Tebas, Kenneth B. Margulies, Frederic D. Bushman, Francis K. Mante, Robert P. Ricciardi, Ronald G. Collman, Mark S. Wolff
Journal: Biomaterials (2022)

Because oral transmission of SARS-CoV-2 is 3-5 orders of magnitude higher than nasal transmission, we investigated debulking of oral viruses using viral trap proteins (CTB-ACE2, FRIL) expressed in plant cells, delivered through the chewing gum. In omicron nasopharyngeal (NP) samples, the microbubble count (based on N-antigen) was significantly reduced by 20 μg of FRIL (p < 0.0001) and 0.925 μg of CTB-ACE2 (p = 0.0001). Among 20 delta or omicron NP samples, 17 had virus load reduced below the detection level of spike protein in the RAPID assay, after incubation with the CTB-ACE2 gum powder. A dose-dependent 50% plaque reduction with 50-100 ng FRIL or 600-800 μg FRIL gum against Influenza strains H1N1, H3N2, and Coronavirus HCoV-OC43 was observed with both purified FRIL, lablab bean powder or gum. In electron micrographs, large/densely packed clumps of overlapping influenza particles and FRIL protein were observed. Chewing simulator studies revealed that CTB-ACE2 release was time/dose-dependent and release was linear up to 20 min chewing. Phase I/II placebo-controlled, double-blinded clinical trial (IND 154897) is in progress to evaluate viral load in saliva before or after chewing CTB-ACE2/placebo gum. Collectively, this study advances the concept of chewing gum to deliver proteins to debulk oral viruses and decrease infection/transmission.
Structural insights into engineering a T-cell receptor targeting MAGE-A10 with higher affinity and specificity for cancer immunotherapy
Authors: Philip C Simister, Ellen C Border, João F Vieira, Nicholas J Pumphrey
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background T-cell receptor (TCR) immunotherapy is becoming a viable modality in cancer treatment with efficacy in clinical trials. The safety of patients is paramount, so innovative cell engineering methods are being employed to exploit adaptive immunity while controlling the factors governing antigen receptor (ie, TCR) specificity and cross-reactivity. We recently reported a TCR engineering campaign and selectivity profiling assay (X-scan) targeting a melanoma antigen gene (MAGE)-A10 peptide. This helped to distinguish between two well-performing TCRs based on cross-reactivity potential during preclinical drug evaluation, allowing one to be advanced to T-cell immunotherapeutic clinical trials. Here, we present three-dimensional structural information on those TCRs, highlighting engineering improvements and molecular mechanisms likely underpinning differential selectivity. Methods Parental and engineered TCRs were purified and crystallized either alone or complexed to human leucocyte antigen (HLA)-A*02:01 presenting the MAGE-A10 9-mer peptide, GLYDGMEHL (pHLA/MAGE-A10-9). Using X-ray diffraction, we solved four high-resolution crystal structures and evaluated them relative to previously reported functional results. Results The unligated parental TCR displayed similar complementarity-determining region (CDR) loop conformations when bound to pHLA/MAGE-A10-9; a rigid-body movement of TCR beta chain variable domain (TRBV) relative to TCR alpha chain variable domain helped optimal pHLA engagement. This first view of an HLA-bound MAGE-A10 peptide revealed an intrachain non-covalent ‘staple’ between peptide Tyr3 and Glu7. A subtle Glu31-Asp mutation in βCDR1 of the parental TCR generated a high-affinity derivative. Its pHLA-complexed structure shows that the shorter Asp leans toward the pHLA with resulting rigid-body TRBV shift, creating localized changes around the peptide’s C-terminus. Structural comparison with a less selective TCR indicated that differential cross-reactivity to MAGE-A10 peptide variants is most readily explained by alterations in surface electrostatics, and the size and geometry of TCR-peptide interfacial cavities. Conclusions Modest changes in engineered TCRs targeting MAGE-A10 produced significantly different properties. Conformational invariance of TCR and antigen peptide plus more space-filling CDR loop sequences may be desirable properties for clinically relevant TCR–pHLA systems to reduce the likelihood of structurally similar peptide mimics being tolerated by a TCR. Such properties may partially explain why the affinity-enhanced, in vitro-selected TCR has been generally well tolerated in patients.
Oncolytic immunotherapy: multiple mechanisms of oncolytic peptides to confer anticancer immunity
Authors: Tianyu Tang, Xing Huang, Gang Zhang, Tingbo Liang
Journal: Journal for ImmunoTherapy of Cancer (2022)

Oncolytic peptides are highly effective on remodeling the tumor microenvironment and potentiating the anticancer immunity through multiple mechanisms, particularly by inducing immunogenic cell death. Intriguingly, a recent study demonstrates that LTX-315, one of the most promising and extensively studied oncolytic peptides, inhibits PD-L1 expression via ATP11B, thus enhancing the effectiveness of cancer immunotherapy by targeting the PD-1/PD-L1 axis. Therefore, this commentary discusses the broad effects and perspectives of oncolytic peptides on anticancer immunity, further highlighting the potential issues and directions of oncolytic peptides in cancer immunotherapy.
ROS-responsive hydrogel coating modified titanium promotes vascularization and osteointegration of bone defects by orchestrating immunomodulation
Authors: Xuan Li, Kun Xu, Ye He, Bailong Tao, Ke Li, Chuanchuan Lin, Jingwei Hu, Jing Wu, Yi Wu, Shaopeng Liu, Peng Liu, Huaiyu Wang, Kaiyong Cai
Journal: Biomaterials (2022)
CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer
Authors: Weilin Sun, Xi Wang, Daohan Wang, Li Lu, Hai Lin, Zhaoxiong Zhang, Yangpu Jia, Xinyang Nie, Tong Liu, Weihua Fu
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background There was much hard work to study the trastuzumab resistance in HER2-positive gastric cancer (GC), but the information which would reveal this abstruse mechanism is little. In this study, we aimed to investigate the roles of tumor cell-derived CCL2 on trastuzumab resistance and overcome the resistance by treatment with the anti-CD40-scFv-linked anti-HER2 (CD40 ×HER2) bispecific antibody (bsAb). Methods We measured the levels of CCL2 expression in HER2-positive GC tissues, and revealed biological functions of tumor cell-derived CCL2 on tumor-associated macrophages (TAMs) and the trastuzumab resistance. Then, we developed CD40 ×HER2 bsAb, and examined the targeting roles on HER2 and CD40, to overcome the trastuzumab resistance without systemic toxicity. Results We found the level of CCL2 expression in HER2-postive GC was correlated with infiltration of TAMs, polarization status of infiltrated TAMs, trastuzumab resistance and survival outcomes of GC patients. On exposure to CCL2, TAMs decreased the M1-like phenotype, thereby eliciting the trastuzumab resistance. CCL2 activated the transcription of ZC3H12A, which increased K63-linked deubiquitination and K48-linked auto-ubiquitination of TRAF6/3 to inactivate NF-κB signaling in TAMs. CD40 ×HER2 bsAb, which targeted the CD40 to restore the ubiquitination level of TRAF6/3, increased the M1-like phenotypic transformation of TAMs, and overcame trastuzumab resistance without immune-related adversary effects (irAEs). Conclusions We revealed a novel mechanism of trastuzumab resistance in HER2-positive GC via the CCL2-ZC3H12A-TRAF6/3 signaling axis, and presented a CD40 ×HER2 bsAb which showed great antitumor efficacy with few irAEs.
Surgical satisfaction and quality of life outcomes reported by transgender men and women at least one year post gender-affirming surgery: A systematic literature review
Authors: Christienne Javier, Charlie R. Crimston, Fiona Kate Barlow
Journal: International Journal of Transgender Health (2022)

Many transgender women and men undergo gender-affirming surgeries. Existing work shows that early surgery outcomes are generally positive, suggesting high surgical satisfaction and positive quality of life outcomes. Less work, however, examines these outcomes in the longer-term.
Endoscopy International Open – recently published
Journal: Endoscopy (2019)

Comment on:Dual red imaging: a novel endoscopic imaging technology visualizing thick blood vessels in the gastrointestinal wallEndosc Int Open 2019; 07(12): E1632-E1635DOI: 10.1055/a-0749-0075Comment on:Multiple stents are not superior to single stent insertion for pain relief in patients with chronic pancreatitis: a retrospective comparative studyEndosc Int Open 2019; 07(12): E1595-E1604DOI: 10.1055/a-1006-2658Comment on:Endoscopic management of large ileocecal valve lesions over an 18-year intervalEndosc Int Open 2019; 07(12): E1646-E1651DOI: 10.1055/a-0990-9035
Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Understanding the metabolic constraints for T cells to generate energy in the tumor microenvironment may reveal new mechanisms to boost anticancer immunity.Di Biase and colleagues discovered that creatine boost the activity of anticancer T cells.The creatine transporter Slc6a8 gene was highly upregulated by tumor-infiltrating immune cells.Tumors grew more aggressively in mice with Slc6a8 knockedout in T cells.While Slc6a8 knockout T cells infiltrated tumors, they exhibited increased PD-1 expression and reduced production of effector cytokines.Mechanistically, import of creatine served as a critical energy store for rapidly transferring phosphate to ADP to generate ATP.Indeed, supplementation of ATP suppressed the defects of Slc6a8 knockout T cells in vitro.Importantly, administration of creatine alone or in combination with anti-PD1 checkpoint blockade boost the anticancer T-cell response.Expert Commentary: Creatine reduces T-cell exhaustion and increases the effector function of T cells in the tumor microenvironment, synergizing with checkpoint blockade to control cancer progression.